Developmental trajectory of pre-hematopoietic stem cell formation from endothelium

Abstract

<jats:title>Summary</jats:title><jats:p>Hematopoietic stem and progenitor cells (HSPCs) differentiate from hemogenic endothelial (HE) cells through an endothelial to hematopoietic cell transition (EHT). Newly formed HSPCs accumulate in intra-arterial clusters (IACs) before colonizing the fetal liver. To examine the cell and molecular transitions during the EHT, and the heterogeneity of HSPCs within IACs, we profiled ∼37,000 cells from the caudal arteries of embryonic day 9.5 (E9.5) to E11.5 mouse embryos by single-cell transcriptome and chromatin accessibility sequencing. We identified an intermediate developmental stage prior to HE that we termed pre-HE, characterized by increased accessibility of chromatin enriched for SOX, FOX, GATA, and SMAD motifs. A developmental bottleneck separates pre-HE from HE, with RUNX1 dosage regulating the efficiency of the pre-HE to HE transition. Distinct developmental trajectories within IAC cells result in two populations of CD45<jats:sup>+</jats:sup> HSPCs; an initial wave of lympho-myeloid-biased progenitors, followed by precursors of hematopoietic stem cells (pre-HSCs).</jats:p>

De novo generation of macrophage from placenta-derived hemogenic endothelium

“…Similar results were also validated by our 10× Genomics data and IF analysis (Figures S4C and D). Furthermore, we verified that the expression of Hoxa13 is restricted to allantois and cannot be detected in blood progenitors from E8.5 (Pijuan-Sala et al, 2019), EMPs from E9.5 (Zhu et al, 2020) and hematopoietic cells from E10.0 to E12.0 (Figures S4E and F).…”

“…This result indicates that HBC-like-3 10× and -4 10× may be derived from placental Hoxa13 + ECs. Moreover, integral analysis of HBC-like cells in 10×Genomics datasets and yolk sac-EMP scRNAseq datasets reveals that HBC-like-1 10× is transcriptionally similar to yolk sac-EMP, suggesting that it may be derived from yolk sac-EMP (Figure S6F) (Zhu et al, 2020).…”

“…See also Tables S2-S4. (G) Heatmap showing the correlation matrix among our 10× Genomics data and yolk sac EMP scRNA-seq data (Zhu et al, 2020). Scale bars, 5 µm.…”

Hematopoietic stem cells from pluripotent stem cells: Clinical potential, challenges, and future perspectives

“…A recent study demonstrated primitive vascular endothelial cells (at E8) follow a two‐step fate choice to become HSC‐primed HE cells; specification into arterial phenotype followed by a subsequent hemogenic conversion 58 . This transition from pre‐HE to HE stage was further demonstrated through trajectory analyses and genetic perturbation experiments 59 . Here, two distinct subpopulations from intra‐arterial clusters, namely precursors of HSCs and CD45+ lympho‐myeloid‐biased progenitors, were reported, although it is not known whether these subpopulations differentiate from an equivalent or distinct population within the HE.…”

Predictive modeling of single-cell DNA methylome data enhances integration with transcriptome data

“…Many promoter regions have a limited number of CpG sites covered in each single cell and dividing the promoter region into multiple bins further exacerbates the sparsity problem, resulting in either bins with no overlapping calls at all, or insufficient calls to make a reliable estimation of the methylation level of the bins. To alleviate this problem, we resorted to the concept of 'meta-cell', essentially borrowing information from neighboring single cells (Wagner, Yan, and Yanai 2017;van Dijk et al 2018;Gong et al 2018;Zhu et al 2019) . Each meta-cell represents a group of individual cells that are in a similar state with a specific cell in the data (Fig.…”